Biphenyloxy-alkyl-piperidine and azepane derivatives as histamine H(3) receptor ligands.

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Lazewska D, Kaleta M, Schwed JS, Karcz T, Mogilski S, Latacz G, Olejarz A, Siwek A, Kubacka M, Lubelska A, Honkisz E, Handzlik J, Filipek B, Stark H, Kiec-Kononowicz K

Biphenyloxy-alkyl-piperidine and azepane derivatives as histamine H(3) receptor ligands.

Bioorg Med Chem. 2017 Oct 15;25(20):5341-5354. doi: 10.1016/j.bmc.2017.07.058. Epub 2017 Jul 29.

PubMed ID

28797771 [ View in PubMed

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Abstract

Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H(3) receptor. Two series of compounds were obtained with a meta- and a para-biphenyl moiety. The alkyl chain spacer contained five and six carbon atoms. The highest affinity among all compounds was shown by 1-(6-(3-phenylphenoxy)hexyl)azepane (13) with a K(i) value of 18nM. Two para-biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine (14; K(i)=25nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane (16; K(i)=34nM), classified as antagonists in a cAMP accumulation assay (IC(50)=4 and 9nM, respectively), were studied in detail. Compounds 14 and 16 blocked RAMH-induced dipsogenia in rats (ED(50) of 2.72mg/kg and 1.75mg/kg respectively), and showed high selectivity (hH(4)R vs hH(3)R>600-fold) and low toxicity (hERG inhibition: IC(50)>1.70microM; hepatotoxicity IC(50)>12.5microM; non-mutagenic up to 10microM). Furthermore, the metabolic stability was evaluated in vitro on human liver microsomes (HLMs) and/or rat liver microsomes (RLMs). Metabolites produced were analyzed and tentatively identified by UPLC-MS techniques. The results demonstrated easy hydroxylation of the biphenyl ring.